Pyridazine derivatives, manufacturing method and related composition

ABSTRACT

Ultraviolet absorbents and photostabilizers have an excellent absorption ability in a wide range of ultraviolet rays, and also have high stability and high safety. The ultraviolet absorbent and photostabilizer include a pyridazine derivative of the formula (1):                    
     or salts thereof. Also, described are methods for manufacturing said pyridazine derivative and/or this salts thereof comprising the process of reacting at least 10 wt % of 4,5-dichloro-3-hydroxypyridazine or 4,5-dibromo-3-hydroxypyridazine or mixtures thereof with at least 20 vol % of morpholine in reaction solution at 70° C. or higher. The ultraviolet absorbents photostabilizers include said pyridazine derivative and/or salts thereof as effective ingredient. An ultraviolet ray absorption composition and an external preparation for skin are also included.

RELATED APPLICATIONS

This application claims priority from Japanese Patent application No.11-356201, filed Dec. 15, 1999, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to pyridazine derivatives, a method forits manufacture, compositions thereof including ultraviolet absorbentsand photostabilizers, ultraviolet-ray-absorptive compositions andexternal preparations for skin.

BACKGROUND OF THE INVENTION

Ultraviolet rays of wavelength 290 nm or less in sunlight are absorbedby the ozone layer. Accordingly, these do not reach the surface of theearth. However, as the ultraviolet rays of 290 to 400 nm reach thesurface of the earth, these ultraviolet rays have various effects. Inskin chemistry, the ultraviolet rays of the wavelength of 290 nm to 320nm cause the formation of erythema and blistering. It is known thatthese ultraviolet rays cause acceleration of melanism and chromatosis.The long wavelength ultraviolet rays of 320 to 400 nm causes themelanism of skin immediately after irradiation. Also, since the energyreaches to an corium of skin, these ultraviolet rays influence theelastica in the walls of blood vessels and connective tissue. Theseultraviolet rays of middle wavelength to long wavelength accelerate theaging of a skin. Also, it is thought that these ultraviolet rays are acause of the formation of stains, freckles, wrinkles and the like.

To protect the skin from such ultraviolet rays, ultraviolet absorbentshave been used. These ultraviolet absorbents include, for example,benzotriazole derivatives, benzophenone derivatives, salicylic acidderivatives, p-aminobenzoic acid derivatives, cinnamic acid derivatives,and urocanic acid derivatives.

These ultraviolet absorbents are used in photostabilizers of colorant,perfume, drug, etc., in medical supplies and cosmetics.

Also, ultraviolet absorbents are used in fields other than medicalsupplies and cosmetics. For example, they are added to the variousmaterials of coating, dye, pigment, resin, synthetic rubber, latex, filmand fiber. As these are given absorbing ability for ultraviolet rays, aproduct, or paints or films coating a product can be protected from theultraviolet rays. The ultraviolet absorbent is used to maintain qualityby preventing degradation, degeneration and so on by the ultravioletrays.

It is desirable that an ultraviolet absorbent is able to absorb theultraviolet rays of all the wavelength range of 290 nm to 400 nm whichreach the surface of the earth. Also, when an ultraviolet absorbent isincluded in an external preparation for skin, it is important that theultraviolet absorbent is not decomposed by sunlight exposure. Also, itis important that the ultraviolet absorbent does not cause skinirritation.

However, conventional ultraviolet absorbents do not always satisfy thesepreferences. Conventional ultraviolet absorbents sometimes causecoloring and deposition due to ultraviolet rays shielding agents ininorganic powders commonly used in external preparations for skin. Also,a satisfactory photostabilizer compound has been needed.

Also, conventional ultraviolet rays absorbents in other fields sublimateand volatilize by heating during sintering of paints and in the formingof resin. In addition, these absorbents vaporize gradually and becomeless effective with the passing of time, even if it is not heated.

SUMMARY OF THE INVENTION

The present invention is achieved in view of the foregoing prior art.The object of the present invention is to provide an ultravioletabsorbent, a photostabilizer and a manufacturing method, which have anexcellent absorbing ability in the wide ultraviolet rays wavelengthrange, that have high stability and safety. It is a another object ofthe present invention to provide an ultraviolet ray absorptioncomposition including said ultraviolet absorbent. It is further objectof the present invention to provide an external preparation for skinincluding said ultraviolet absorbent or said photostabilizer.

As a result of diligent study by the present inventors, it was foundthat a certain kind of pyridazine derivatives have the above-mentionedproperties and are excellent ultraviolet absorbents andphotostabilizers.

Namely, the present invention is pyridazine derivatives of generalformula (1) and salts thereof. The compound of the present invention hasexcellent absorbing ability with respect to the wide ultraviolet raywavelength range. As it is very stable and safe, it is an excellentultraviolet absorbent and photostabilizer.

A manufacturing method of the pyridazine derivatives comprises theprocess of reacting at least 10 wt % of 4,5-Dichloro-3-hydroxypyridazineor 4,5-Dibromo-3-hydroxypyridazine or combination thereof, with at least20 vol % of morpholine in a reaction solution at 70° C. or higher.

An ultraviolet absorbent of the present invention comprises saidpyridazine derivatives and/or salts thereof as an active ingredient.

An ultraviolet ray absorption composition of the present inventionincludes said ultraviolet absorbents.

A photostabilizer of the present invention comprises said pyridazinederivatives and/or salts thereof, as an active ingredient. It ispreferable that said photostabilizer includes a sequestering agent.

An external preparation for skin of the present invention comprises saidultraviolet absorbents. Also, it is preferable that the externalpreparation for skin of the present invention includes an inorganicpowder.

Also, an external preparation for skin of the present inventioncomprises said photostabilizer. It is preferable that said external skinpreparation includes a sequestering agent.

Also, in the external skin preparation of the present invention, it ispreferable that said external preparation for skin includes 0.001 wt %to 20 wt % of said pyridazine derivatives or salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ultraviolet absorption spectrum of pyridazinederivative (4,5-Dimorpholino-3-hydroxypyridazine) of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Pyridazine DerivativesAnd Salts Thereof

A pyridazine derivative of the present invention is shown in a generalformula (1). This compound can be isomerized to general formula (1′),which is tautomer with the equilibrium like the following, under certainconditions.

The pyridazine derivatives in the present invention are described onlyby the general formula (1) for convenience. However, the pyridazinederivatives in the present invention can be isomerized to a generalformula (1′) as a tautomer.

The chemical name of the pyridazine derivative of the present inventionincludes 4,5-Dimorpholino-3-hydroxypyridazine and4,5-Dimorpholino-3-hydroxypyridazine hydrochloride and the like.

A pyridazine derivative of the present invention can be synthesized bythe followings method.

In the above-mentioned reaction formula, A represents a chlorine atom orbromine atom. The compound of a general formula (3) (when A is achlorine atom, 4,5-Dichloro-3-hydroxypyridazine; when A is a bromineatom, 4,5-Dibromo-3-hydroxypyridazine) can be synthesized by the methodof Chemische Berichte, 32, 543(1899) and so on in accordance with theabove-mentioned formula. The compounds of the general formula (2) can beeasily available. Namely, the compounds of a general formula (3) iseasily obtained by cyclic reaction of compounds of a general formula (2)and hydrazine. Also, the compounds of the general formula (3) (A ischlorine atom) which can be available from ALDRICH Inc. Also, pyridazinederivatives of the present invention were obtained by reacting 10 wt %or more of a compound of the general formula (3) and 20 vol % or more ofmorpholine in a reaction solution at 70° C. or higher. In the case wherethe concentration of compounds of the general formula (3) in thereaction solution is less than 10 wt %, in the case where theconcentration of morpholine in the reaction solution is less than 20 vol%, and in the case where reaction temperature is lower than 70° C., itwas difficult to obtain pyridazine derivatives of the present invention.

Also, the pyridazine derivatives of the present invention includeinorganic acid salt or organic acid salt made by published methods.Examples of inorganic acids include hydrochloric acid, sulfuric acid,phosphoric acid, hydrobromic acid. Examples of organic acids includeacetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid,citric acid, methanesulfonic acid, p-toluenesulfonic acid.

Ultraviolet Absorbent And External Preparation For Skin

An ultraviolet absorbent having as its principal component pyridazinederivative or salt thereof can be included in various products. Anexternal skin preparation including this absorbent is suitable. Anexternal preparation for skin having the ultraviolet absorbent of thepresent invention demonstrates an excellent ultraviolet ray preventioneffect. Also, since the ultraviolet absorbent does not decompose undersunlight exposure, the effect is continued for a long time. Also, itdoes not cause problems for the skin. Accordingly, it is especiallyuseful as the external skin preparation for sun screen.

Also, to increase the ultraviolet rays shielding effect in an externalskin preparation for sun screen, it is preferred that an ultravioletabsorbent of an organic compound and an ultraviolet ray shielding agentof an inorganic powder are included. Also, many cosmetics for makeupinclude inorganic powder. However, use of an organic ultravioletabsorbent and inorganic powder may cause discoloration.

The ultraviolet absorbent of the present invention does not causediscoloration, when included with an inorganic powder in an externalskin preparation for skin. Therefore, it is possible to includeinorganic powder.

Inorganic Powder

In the present invention, an inorganic powder includes powder incosmetics and medical supplies. Examples of inorganic powder includetalc, kaolin, boron nitride, mica, sericite, muscovite, black mica,golden mica, synthetic mica, vermiculite, magnesium carbonate, calciumcarbonate, silicic anhydride, aluminum silicate, aluminum oxide, bariumsilicate, calcium silicate, magnesium cilicate, tungsten metal salt,magnesium, silica, zeolite, barium sulfate, calcined calcium sulfate,calcined gypsum, calcium phosphate, fluoroapatite, calcium phosphatehydroxide, ceramic powder, metal soap (zinc myristate, calciumpalmitate, aluminum stearate etc.). Also, examples of inorganic pigmentinclude titanium dioxide, zinc oxide, iron oxide, iron titanium oxide,carbon, low-valent titanium oxide, mango violet, cobalt violet, chromiumoxide, chromium hydroxide, cobalt titanium oxide, ultramarine, ironblue, titanium oxide coated mica, titanium oxide coated bismuthoxychloride, colored titanium oxide coated mica, bismuth oxychloride,fish scale flake.

Photostabilizer

The pyridazine derivatives and salts thereof of the present inventionare useful as a photostabilizer. Especially, the compound is anexcellent photostabilizer of colorants, perfumes and drugs in medicalsupplies and cosmetics. Also, the pyridazine derivatives and saltsthereof of the present invention can achieve a synergisticphotostabilization effect, by including a sequestering agent.

Sequestering Agent

In the present invention, pyridazine derivatives or salts thereof can beused with a sequestering agent. Examples of sequestering agents includesodium ethylenediaminetetraacetate (EDTA), trisodium hydroxyethylethylenediamine triacetate(dihydrate), phosphoric acid, citric acid,ascorbic acid, succinic acid, gluconic acid, sodium polyphosphate,sodium metaphosphate, 1-hydroxyethane 1,1-diphosphate.

Use Of External Preparation For Skin

The external preparation for skin of the present invention may includesthe above-mentioned ultraviolet absorbent or the above-mentionedphotostabilizer. Forms of the external preparation for skin of thepresent invention are not restricted if the effect of the presentinvention is demonstrated. Examples of forms of the external preparationfor skin of the present invention include lotion, milky lotion, creamand essence for skin care cosmetics. Also, examples of makeup cosmeticsinclude base cosmetics, foundation, lipstick, face color and eyeliner.Also, examples of cosmetics for hair and scalp include hair spray, hairtonic and hair liquid.

Amount Of Pyridazine Derivative Or Salts Thereof In An External SkinPreparation

When the external preparation for skin includes the pyridazinederivatives and/or salts thereof of the present invention, the amountdepends on the need for UV absorbing ability or photostabilizationability. Usually the preferable amount of pyridazine derivative and/orsalt thereof in a composition is 0.001 wt % to 20 wt %, more preferably0.01 wt % to 10 wt %. If the amount is less than 0.001 wt %, theultraviolet rays prevention effect or photostabilization effect mayinadequate. Also, if the amount is more than 20 wt %, it may bedifficult to maintain the form of external skin preparation.

Other Ingredients

The external preparation for skin of the present invention can includeother ingredients often included in cosmetics and medical supplies.Examples of other ingredients include liquid fat and oil, solid fat andoil, wax, hydrocarbon, higher fatty acid, higher alcohol, ester,silicone, anionic surfactant, cationic surfactant, ampholyticsurfactants, nonionic surfactant, humectants, water-soluble highmolecular compounds, thickeners, film formers, lower alcohol, polyhydricalcohol, saccharides, amino acid, organic amine, pH adjustment agent,skin nutrition agents, vitamins, antioxidants, perfumes, powder,colorants and water and the like. These ingredients can be combined inexternal preparation for skin of the present invention if needed. Also,ultraviolet absorbents and photostabilizers other than the pyridazinederivatives of the present invention can be combined unless the objectsof the invention are thwarted.

Ultraviolet Absorptive Composition

The ultraviolet absorbent of the present invention can be used inproducts other than external skin preparation. For example, coating,dye, pigment, resin, synthetic rubber, latex, film, fiber and so on caninclude the ultraviolet absorbent of the present invention forultraviolet ray prevention. Since pyridazine derivatives of the presentinvention excel in heat stability without vaporizing, the effect can bemaintained for a long time. The preferable amount in this case isusually 0.00 wt % to 20 wt %, more preferably 0.01 wt % to 10 wt %. Ifthe amount is less than 0.001 wt %, the ultraviolet ray defense effectmay be inadequate. If the amount is greater than 20 wt %, it may bedifficult to form of the external skin preparation.

The present invention is explained in more fully by the followingexamples, but, the present invention is not restricted to theseexamples. The following are the manufacturing examples of pyridazinederivatives of the present invention.

1 A method synthesizing a 4,5-Dimorphorino-3-hydroxypyridazine

4,5-Dichloro-3-hydroxypyridazine (25.0 g, 0.151 mol=about 17 wt % inreaction solusion) was dissolved to morpholine (120 ml=100 vol %). Themixture was heated at 70° C. or more for 24 hours. After being cooled,deposited crystal was filtered. White crystal of4,5-Dimorpholibo-3-hydroxypyridazine (37.2 g, yield percentage 92%) wasobtained.

Melting point 256 to 257° C. (Decomposition) (Capil.)

Next, chemical analysis values of the obtained compound were shown.Table 1 shows the result of elemental analysis. Next, the results of¹H—NMR, ¹³C—NMR and MS spectra were shown. These chemical data supportthe desired compound.

TABLE 1 Elemental analysis value C (%) H (%) N (%) Calcd. (*) (%) 54.126.81 21.04 Found (%) 54.25 6.72 21.11 (*): Calcd. for C₁₂H₁₈N₄O₃

¹H—NMR(DMSO—d₆, TMS, ppm)

δ: 3.21 (dd, 4H, J=4.4&4.9Hz: —CH₂—N—CH₂—),

3.23 (dd, 4H, J=4.4&4.9Hz: —CH₂—N—CH₂—),

3.62 (dd, 4H, J=4.4&4.9Hz: —CH₂—O—CH₂—),

3.70 (dd, 4H, J=4.4&4.9Hz: —CH₂—O—CH₂—),

7.67 (s, 1H: pyridazine ring H-6), 12.38 (s, 1H: OH)

¹³C—NMR: (DMSO—d₆, TMS, ppm)

δ: 47.8 (—CH₂—N—CH₂—), 48.5 (—CH₂—N—CH₂—), 66.1 (—CH₂—O—CH₂—),66.6(—CH₂—O—CH₂—), 131.1, 132.6, 141.0(pyridazine ring C-4, C-5, C-6),160.7 (pyridazine ring C-3)

MS spectrum: MW=266(C₁₂H₁₈N₄O₃=266.30)

2 A method synthesizing a 4,5-Dimorpholino-3-hydroxyPyridazine

4,5-Dibromo-3-hydroxypyridazine (25.0 g, 0.098 mol=about 17 wt % inreaction solution) was dissolved to morpholine (120 ml=100 vol %). Themixture was heated at 70° C. or higher for 24 hours. After being cooled,deposited crystal was filtered. White crystal of4,5-Dimorpholibo-3-hydroxypyridazine (23.7 g, yield percentage 90%) wasobtained.

Melting point 256 to 257° C. (Decomposition) (Capil.)

Next, chemical analysis values for the obtained compound are shown.Table 2 shows the result of elementary analysis. Next, the results of¹H—NMR, ¹³C—NMR and MS spectra were shown. These chemical data supportthe desired components.

TABLE 2 Elemental analysis value C (%) H (%) N (%) Calcd. (*) (%) 54.126.81 21.04 Found (%) 54.22 6.82 21.09 (*): Calcd. for C₁₂H₁₈N₄O₃

¹H—NMR(DMSO—d₆, TMS, ppm)

δ: 3.21 (dd, 4H, J=4.4&4.9 Hz: —CH₂—N—CH₂—),

3.23 (dd, 4H, J=4.4&4.9Hz: —CH₂—N—CH₂—),

3.62 (dd, 4H, J=4.4&4.9 Hz: —CH₂—O—CH₂—),

3.70 (dd, 4H, J=4.4&4.9 Hz: —CH₂—O—CH₂—),

7.67 (s, 1H: pyridazine ring H-6), 12.38(s, 1H:OH)

¹³C—NMR: (DMSO—d₆, TMS, ppm)

δ: 47.8 (—CH₂—N—CH₂—), 48.5(—CH₂—N—CH₂—), 66.1 (—CH₂—O—CH₂—),

66.6 (—CH₂—O—CH₂—), 131.1, 132.6,

141.0 (pyridazine ring C-4, C-5, C-6),

160.7 (pyridazine ring C-3)

MS spectrum: MW=266(C₁₂H₁₈N₄O₃=266.30)

Next, test result for ultraviolet rays absorbing ability of thepyridazine derivatives of the present invention are shown.

Test 1 Absorption

Ultraviolet rays absorption spectrum of4,5-Dimorpholino-3-hydroxypyridazine (Solvent: water, Concentration: 10ppm, Light path: 1 cm) was measured by the spectrophotometer(Manufactured by Nihonbunko Inc., Trade name: Ubest-55). The result wasshown in FIG. 1.

FIG. 1 shows that a pyridazine derivative of the present invention canabsorb strongly with respect to the entire wavelength range ofultraviolet rays, 290 nm to 400 nm, which reach the surface of theearth. Also, it shows hardly any absorption in visible range forwavelengths longer than 400 nm. Accordingly, pyridazine derivatives ofthe present invention is excellent in visual transparency.

Test Example 2 Ultraviolet Rays Prevention Effect

(i) Test method

The prevention effect test was carried out on a beach during the summer.Equal amounts of sample were applied to the right and left sides of thebacks of test subjects. After direct sunlight exposure, the degree ofsunburn was evaluated in accordance with the following criteria. Eachgroup consisted of 20 subjects.

(Criterion)

Remarkable effect: None or almost no sunburn symptom was found.

Positive effect: Slight sunburn symptom was found.

Negative effect: Strong sunburn symptom was found.

(Evaluation)

A: Subject of remarkable effect or positive effect is 80% or more.

B: Subject of remarkable effect or positive effect is 50% or more andless than 80%.

C: Subject of remarkable effect or positive effect is 30% or more andless than 50%.

D: Subject of remarkable effect or positive effect is less than 30%

(ii) Preparation of sample

(A) Lotion

(Alcohol phase) 95% Ethanol 25.0 (wt %) Polyoxyethylene(25) hydrogenatedcastor oil  2.0 Ultraviolet absorbent (See Table 3)  0 to 20 Antisepticsq.s. Perfume q.s. (Water phase) Glycerol  5.0 Sodium hexametaphosphateq.s. Ion-exchanged water Balance (Manufacturing method)

Each of water phase and alcohol phase was prepared. Then each was mixed.

(B) Cream

Stearyl alcohol 7.0 (wt %) Stearic acid 2.0 Hydrogenated Lanolin 2.0Squalane 5.0 2-Octyldodecyl alcohol 6.0 Polyoxyethylene(25) cetyl ether3.0 Glyceryl monostearate 2.0 Propylene glycol 5.0 Ultraviolet absorbent(See Table 4) 0 to 20 Perfume q.s. Sodium hydrogensulfite 0.03 Ethylparaben 0.3 Ion-exchanged water Balance (Manufacturing method)

The propylene glycol was added to ion-exchanged water and was dissolved,which was kept at 70° C. by heating (Water phase). The other componentswere mixed and melted by heating and was kept at 70° C. (Oil phase). Theoil phase was added to the water phase, and an emulsion was formed..After it was homogeneously emulsified with a homogenixer, it was cooledat 30° C. with stirring well.

(iii) Result

The result with regard to lotion (a), cream (b) were shown in Table 3and 4, respectively.

TABLE 3 UV Ultraviolet absorbent Amount (wt %) prevent effect4,5-dimorpholino-3-hydroxypyridazine 20 A 10 A 5 A 1 A 0.01 A 0.001 B0.0005 C No combination 0 D

TABLE 4 UV Ultraviolet absorbent Amount (wt %) prevent effect4,5-dimorpholino-3-hydroxypyridazine 20  A 10 A 5 A 1 A 0.1 A 0.001 B0.0005 C No combination 0 D

Table 3 and Table 4 show that external skin preparation including apyridazine derivative of the present ultraviolet ray prevention effectas an ultraviolet absorbent. Also, it shows that the preferable amountof pyridazine derivative and/or salt thereof of the present invention is0.001 wt % to 20 wt %. Also, having an amount greater than 20 wt % makesit difficult to form an external skin preparation.

Accordingly, the pyridazine derivatives of the present invention haveexcellent absorbing ability with regard to wide range of ultravioletrays. The inventors have studied with regard to the amount of thepresent invention in an ultraviolet absorbent in external skinpreparation. The inventors have studied it with regard to skinirritation, photostability and inorganic powder.

Test Example 3 Skin Irritation Test

Sample (10 wt % of ultraviolet absorbent) is the same as test example 2.

(i ) Continuous use test

The continuous use test by the healthy subjects was carried out with onegroup of twenty subjects. A proper amount of each sample was applied tothe face twice a day for 4 weeks. The evaluation standard of Table 5 wasjudged.

TABLE 5 Degree of skin reaction Score No symptom (Negative) 0 Veryslight symptom (false negative) 1 Slight symptom (weak positive) 2Middle symptom (middle positive) 3 Strong symptom (strong positive) 4

(Evaluation)

The calculated average score was evaluated by the next standard.

A: Average score is 0.

B: Average score is over 0 and less than 1.

C: Average score is 1 or more, and less than 2.

D: Average score is 2 or more.

The result was shown in Table 6.

TABLE 6 Ultraviolet absorbent Formulation Judgment4,5-dimorpholino-3-hydroxypyridazine Lotion A Cream A No combinationLotion A Cream A

(ii) Patch test

An occlusive patch test was carried out in the antebrachium part ofhealthy men and women subjects by finchamber for 24 hours. Each groupwas twenty subjects. The judgement standard is shown in Table 7.

TABLE 7 Degree of skin reaction Score No reaction (Negative) 0 Slighterythema (false positive) 1 Erythema (weak positive) 2 Erythema + edema(Middle degree positive) 3 Erythema + edema + papula (Strong positive) 4Erythema bullosum (Most strong positive) 5

(Evaluation)

Each of the calculated average scores was evaluated by the followingevaluation standard.

A: average score is 0.

B: average score is over 0 and less than 1.

C: average score is 1 or more and less than 2.

D: average score is 2 or more.

The result was shown in Table 8.

TABLE 8 Ultraviolet absorbent Formulation Judgment4,5-dimorpholino-3-hydroxypyridazine Lotion A Cream A No combinationLotion A Cream A

Table 6 and Table 8 shows that external preparation for skin includingultraviolet absorbent of the present invention does not cause skinirritation in continuous use test and patch test, Also, it is understoodthat external preparation for skin of the present is very safe.

Test Example 4 Photostability Test

After an aqueous solution of the pyridazine derivative of the presentinvention was exposed to sunlight (Amount of solar radiation exposure 80MJ/m²) for two weeks, residual yield and change of appearance werechecked. UV absorption spectrum (Solvent: water, concentration: 10 ppm,Light path: 1 cm) was measured by spectrophotometer. Area value wascalculated by integrating over the range of 290 nm to 400 nm of theultraviolet rays absorption spectrum. The area value was compared withthe value before sunlight exposure.

(Evaluation standard)

The residual yield and change of area value of ultraviolet raysabsorption spectrum were evaluated by the following standard.

A: 95% or more of area value before sunlight exposure.

B: 90% or more and less than 95% of area value before sunlight exposure.

C: 70% or more and less than 90% of area value before sunlight exposure.

D: less than 70% of area value before sunlight exposure.

The result was shown in Table 9.

TABLE 9 Change of area value of Ultraviolet absorbent Residual yield UVabsorption spectrum 4,5-dimorpholino-3- A A hydroxypyridazine

Table 9 shows that a pyridazine derivative of the present invention hasa very high residual yield. Accordingly, pyridazine derivative of thepresent invention did not decomposed by direct sunlight exposure for along time. Also, the shape and area value of ultraviolet ray absorptionspectrum did not change. Also, coloring and deposition and so on in theappearance were not found.

Test Example 6 Stability Test In Case Of Including UV Shielding Agent OfInorganic Powder

The sun screen cream of the following formulation was manufactured.These were preserved for 2 months at 50° C. By visual observation ofdiscoloration, the inventors have checked stability when using an UVshielding agent of inorganic powder which is included as external skinpreparation for the ultraviolet rays defense.

Sun-screen cream  (1) Ethyl cellulose  1.0 (wt %)  (2) Ethanol  5.0  (3)2-Ethylhexyl succinate 24.0  (4) Titanium dioxide  1.0  (5) Poroussilicic anhydride powder  1.0  (6) Spherical nylon powder  1.0  (7) Talc 1.0  (8) Sericite  1.0  (9) Boron nitride  1.0 (10) Silicone treatedmica  1.0 (11) Ultraviolet absorbent (See Table 10) 10.0 (12)Carboxymethylcellulose  1.0 (13) Ion-exchanged water Balance (14)Antiseptics q.s. (15) Perfume q.s.

(Manufacturing method)

After (2) was added to (1) and was swelled sufficiently, (3) to (11) wasadded thereto and was mixed with heating. The mixture was sufficientlydissolved with dispersing. This dispersed liquid was kept at 70° C.After this dispersed liquid was emulsified homogeneously by homomixerwith adding a mixture of (12) to (15) gradually, which was cooled to 30°C. with stirring well to obtain sun screen.

The result was shown in Table 10.

TABLE 10 Ultraviolet absorbent Discoloration4,5-Dimorpholino-3-hydroxypyridazine No

Table 10 shows that discoloration is not found in a pyridazinederivative of the the present invention in the case where inorganicpowder is used.

Accordingly, pyridazine derivatives of the present invention do notcause skin irritation and excel in photostability. Also, discolorationdoes not result in case of use of inorganic powder. Accordingly,pyridazine derivatives of the present invention are very useful as anultraviolet absorbent in an external skin preparation.

Next, the effect as a photostabilizer of pyridazine derivative of thepresent invention was studied.

First of all, the photostabilization effect and appearance change of acomposition in each pigment were studied by the following evaluationformulation.

Formulation for Evaluation of Colorant Stabilization Effect

Material Amount (wt %) Ion-exchanged water to 100 Brucine denaturedalcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylene hydrogenatedcastor oil 1 Methyl paraben 0.2 Lactic acid 0.006 Sodium lactate 0.2Photo-stabilizer (See Table 11 to 16) See Table 11 to 16 Pigment (SeeTable 11 to 16) See Table 11 to 16 Total 100 

Each test sample was prepared. Observation of appearance change (visualevaluation) and measurement of color difference (ΔE) were carried out insamples exposed to sunlight exposure (around 80 MJ).

Color difference was measured by Lab coordinate system withspectrophotometer. Color difference was calculated on the basis of thecolor before sunlight exposure. Namely, from measured value (L₁,a₁,b₁)before sunlight exposure, color difference (ΔE) was calculated byfollowing formula.

ΔE={(L₂−L₁)²+(a₂−a₁−a₁)²+(b₂−b₁)²}^(½)

Table 11 and Table 12 show the result of the combination of a singlecolorant and various kinds of photostabilizer.

TABLE 11 Sunlight exposure Test Colorant Photostabilizer (80 MJ) exampleName Amount Name Amount ΔE Appearance  7 Red No. 227 0.0001 No 0 1.45 C 8 (D&C Red No. 33) 4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.49 A  9(Trade name: Fast Acid Magenta) 2-Hydroxy-4-methoxybenzophenone 0.050.71 B 10 2-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.80 B11 Octyl p-methoxycinnamate 0.05 1.22 C 124-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.95 B 13 Red No. 1060.0001 No 0 3.04 C 14 (Trade name: Acid Red 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.82 A 152-Hydroxy-4-methoxybenzophenone 0.05 1.01 B 162-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.98 B 17 Octylp-methoxycinnamate 0.05 1.95 C 184-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02 B 19 Yellow No. 2030.001 No 0 2.77 C 20 (D&C Yellow No. 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.18 A 21 (Trade name:Quinoline Yellow WS) 2-Hydroxy-4-methoxybenzophenone 0.05 0.88 B 222-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.76 B 23 Octylp-methoxycinnamate 0.05 2.43 C 244-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.68 B 25 Yellow No. 50.001 No 0 1.83 C 26 (FD&C Yellow No. 6)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.43 A 27 (Trade name: SunsetYellow FCF) 2-Hydroxy-4-methoxybenzophenone 0.05 0.82 B 282-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.78 B 29 Octylp-methoxycinnamate 0.05 1.56 C 304-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.88 B Appearance(Evaluation by vision)  A: No change  B: No almost change  C: Yes change

TABLE 12 Sunlight exposure Test Colorant Photostabilizer (80 MJ) exampleName Amount Name Amount ΔE Appearance 31 Blue No. 1 0.0001 No 0 8.92 C32 (FD&C Blue No. 1) 4,5-Dimorpholino-3-hydroxypyridazine 0.05 1.11 A 33(Trade name: Brilliant Blue FCF) 2-Hydroxy-4-methoxybenzophenone 0.051.76 B 34 2-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 1.67 B35 Octyl p-methoxycinnamate 0.05 5.23 C 364-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.49 B 37 Green No. 30.0001 No 0 2.12 C 38 (FD&C Green No. 3)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.31 A 39 (Trade name: FastGreen FCF) 2-Hydroxy-4-methoxybenzophenone 0.05 0.75 B 402-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.74 B 41 Octylp-methoxycinnamate 0.05 1.64 C 424-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.62 B 43 Red No. 2130.0001 No 0 3.79 C 44 (D&C Red No. 19)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.78 A 45 (Trade name:Rhodamine B) 2-Hydroxy-4-methoxybenzophenone 0.05 1.34 B 462-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 1.28 B 47 Octylp-methoxycinnamate 0.05 2.55 C 484-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02 B 49 Red No. 4010.001 No 0 7.58 C 50 (Ext. D&C Red No. 3)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.71 A 51 (Trade name:Violamine R) 2-Hydroxy-4-methoxybenzophenone 0.05 1.18 B 522-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 1.39 B 53 Octylp-methoxycinnamate 0.05 4.76 C 544-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02 B Appearance(Evaluation by vision)  A: No change  B: No almost change  C: Yes change

Next, Table 13 shows the result of the combination of multiple pigmentsand various kinds of photostabilizer.

TABLE 13 Sunlight exposure Test Colorant Photostabilizer (80 MJ) exampleName Amount Name Amount ΔE Appearance 55 Red No. 227 0.0001 No 0 1.59 C56 (Trade name: Fast Acid Magenta) 4,5-Dimorpholino-3-hydroxypyridazine0.05 0.59 A 57 Yellow No. 5 0.0001 2-Hydroxy-4-methoxybenzophenone 0.050.88 B 58 (Trade name: Sunset Yellow FCF)4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.80 B 59 Red No. 2270.0001 No 0 3.05 C 60 (Trade name: Fast Acid Magenta)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.78 A 61 Yellow No. 2030.0001 2-Hydroxy-4-methoxybenzophenone 0.05 1.05 B 62 (Trade name:Quinoline Yellow WS) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.12B 63 Red No. 106 0.00001 No 0 3.77 C 64 (Trade name: Acid Red 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.77 A 65 Yellow No. 2030.0001 2-Hydroxy-4-methoxybenzophenone 0.05 1.11 B 66 (Trade name:Quinoline Yellow WS) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02B 67 Red No. 106 0.00001 No 0 4.45 C 68 (Trade name: Acid Red 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.55 A 69 Yellow No. 5 0.00012-Hydroxy-4-methoxybenzophenone 0.05 1.18 B 70 (Trade name: SunsetYellow FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.92 B 71Yellow No. 203 0.0001 No 0 1.45 C 72 (Trade name: Quinoline Yellow WS)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.37 A 73 Yellow No. 5 0.00012-Hydroxy-4-methoxybenzophenone 0.05 0.52 A 74 (Trade name: SunsetYellow FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.48 A 75 RedNo. 213 0.00001 No 0 3.89 C 76 (Trade name: Rhodamine B)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.97 A 77 Blue No. 1 0.000012-Hydroxy-4-methoxybenzophenone 0.05 1.26 B 78 (Trade name: BrilliantBlue FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.17 B 79 RedNo. 401 0.0001 No 0 3.04 C 80 (Trade name: Violamine R)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.32 A 81 Blue No. 1 0.000012-Hydroxy-4-methoxybenzophenone 0.05 0.82 B 82 (Trade name: BrilliantBlue FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.93 B 83 RedNo. 401 0.0001 No 0 4.54 C 84 (Trade name: Violamine R)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.73 A 85 Green No. 3 0.000012-Hydroxy-4-methoxybenzophenone 0.05 1.06 B 86 (Trade name: Fast GreenFCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.99 B Appearance(Evaluation by vision)  A: No change  B: No almost change  C: Yes change

Tables 11 to 13 show that the color difference ΔE in a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention is very small in comparison with other photostabilizers. Also,the change of appearance of the composition is small. Accordingly, it isunderstood that pyridazine derivative of the present invention hasexcellent photo stability for colorant.

Next, the inventors studied the effective amount of photostabilizer ofthe present invention for pigment. Table 14 and Table 15 show the resultof combination of a pyridazine derivative of the present invention and asingle colorant.

TABLE 14 Sunlight Test Colorant Photostabilizer exposure (80 MJ) exampleName Amount Name Amount ΔE Appearance  87 Red No. 227 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 1.45 C  88 (D&C Red No. 33) 0.020.71 A  89 (Trade name: Fast Acid Magenta) 0.05 0.49 A  90 0.1 0.22 A 91 0.00001 0 2.35 C  92 0.05 0.69 A  93 0.1 0.32 A  94 0.3 0.11 A  95Red No. 106 0.0001 4,5-Dimorpholino-3-hydroxypyridazine 0 3.04 C  96(Trade name: Acid Red 52) 0.03 0.95 A  97 0.05 0.82 A  98 0.1 0.43 A  990.00001 0 4.54 C 100 0.05 1.01 A 101 0.1 0.55 A 102 0.3 0.12 A 103Yellow No. 203 0.001 4,5-Dimorpholino-3-hydroxypyridazine 0 2.77 C 104(D&C Yellow No. 10) 0.02 0.25 A 105 (Trade name: Quinoline Yellow WS)0.05 0.18 A 106 0.1 0.08 A 107 0.0001 0 3.52 C 108 0.05 0.22 A 109 0.10.10 A 110 0.3 0.05 A 111 Yellow No. 5 0.0014,5-Dimorpholino-3-hydroxypyridazine 0 1.83 C 112 (FD&C Yellow No. 6)0.01 0.61 A 113 (Trade name: Sunset Yellow FCF) 0.05 0.43 A 114 0.1 0.22A 115 0.0001 0 2.54 C 116 0.05 0.59 A 117 0.1 0.71 A 118 0.3 0.22 AAppearance (Evaluation by vision)  A: No change  B: No almost change  C:Yes change

TABLE 15 Sunlight Test Colorant Photostabilizer exposure (80 MJ) exampleName Amount Name Amount ΔE Appearance 119 Blue No. 1 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 8.92 C 120 (FD&C Blue No. 1) 0.031.25 A 121 (Trade name: Brilliant Blue FCF) 0.05 1.11 A 122 0.1 0.70 A123 0.00001 0 8.02 C 124 0.05 1.00 A 125 0.1 0.62 A 126 0.3 0.25 A 127Green No. 3 0.0001 4,5-Dimorpholino-3-hydroxypyridazine 0 2.12 C 128(FD&C Green No. 3) 0.02 0.75 A 129 (Trade name: Fast Green FCF) 0.050.31 A 130 0.1 0.06 A 131 0.00001 0 3.02 C 132 0.03 0.56 A 133 0.1 0.08A 134 0.3 0.02 A 135 Red No. 213 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.79 C 136 (D&C Red No. 19) 0.031.11 B 137 (Trade name: Rhodamine B) 0.05 0.78 A 138 0.1 0.32 A 1390.00001 0 4.57 C 140 0.03 1.24 B 141 0.1 0.45 A 142 0.3 0.12 A 143 RedNo. 401 0.001 4,5-Dimorpholino-3-hydroxypyridazine 0 7.58 C 144 (Ext.D&C Red No. 3) 0.03 0.95 A 145 (Trade name: Violamine R) 0.05 0.71 A 1460.1 0.45 A 147 0.0001 0 8.28 C 148 0.05 0.82 A 149 0.1 0.56 A 150 0.30.19 A Appearance (Evaluation by vision)  A: No change  B: No almostchange  C: Yes change

Table 16 shows the result of combining a pyridazine derivative of thepresent invention and multiple colorant.

TABLE 16 Sunlight Test Colorant Photostabilizer exposure (80 MJ) exampleName Amount Name Amount ΔE Appearance 151 Red No. 227 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 1.59 C 152 (Trade name: Fast AcidMagenta) 0.03 0.72 A 153 Yellow No. 5 0.0001 0.05 0.59 A 154 (Tradename: Sunset Yellow FCF) 0.1 0.18 A 155 Red No. 227 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.05 C 156 (Trade name: Fast AcidMagenta) 0.05 0.78 A 157 Yellow No. 203 0.0001 0.1 0.35 A 158 (Tradename: Quinoline Yellow WS) 0.3 0.14 A 159 Red No. 106 0.000014,5-Dimorpholino-3-hydroxypyridazine 0 3.77 C 160 (Trade name: Acid Red52) 0.05 0.77 A 161 Yellow No. 203 0.0001 0.1 0.25 A 162 (Trade name:Quinoline Yellow WS) 0.3 0.11 A 163 Red No. 106 0.000014,5-Dimorpholino-3-hydroxypyridazine 0 4.45 C 164 (Trade name: Acid Red52) 0.03 0.97 A 165 Yellow No. 5 0.0001 0.05 0.55 A 166 (Trade name:Sunset Yellow FCF) 0.3 0.12 A 167 Yellow No. 203 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 1.45 C 168 (Trade name: QuinolineYellow WS) 0.03 0.52 A 169 Yellow No. 5 0.0001 0.05 0.37 A 170 (Tradename: Sunset Yellow FCF) 0.1 0.12 A 171 Red No. 213 0.000014,5-Dimorpholino-3-hydroxypyridazine 0 3.89 C 172 (Trade name: RhodamineB) 0.03 1.21 A 173 Blue No. 1 0.00001 0.05 0.97 A 174 (Trade name:Brilliant Blue FCF) 0.1 0.73 A 175 Red No. 401 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.04 C 176 (Trade name: ViolamineR) 0.03 0.95 A 177 Blue No. 1 0.00001 0.05 0.32 A 178 (Trade name:Brilliant Blue FCF) 0.1 0.07 A 179 Red No. 401 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 4.54 C 180 (Trade name: ViolamineR) 0.03 0.98 A 181 Green No. 3 0.00001 0.05 0.73 A 182 (Trade name: FastGreen FCF) 0.3 0.14 A Appearance (Evaluation by vision)  A: No change B: No almost change  C: Yes change

Tables 14 to 16 show that approximately 0.01 wt % to approximately 0.3wt % of pyridazine derivatives of the present invention is effective asa photostabilizer in approximately 0.00001 wt % to approximately 0.001wt % of colorant. Also, although over 0.3 wt % of pyridazine derivativeis possible, in case of external preparation for skin, if the amount isgreater than 20 wt % of pyridazine derivative, it is difficult tomaintain the formulation of the external skin preparation.

Next, the photostabilization effect for each perfume was studied by thefollowing evaluation formulation.

Formulation For Evaluation Of Perfume Stabilization Effect

Material Amount (wt %) Ion-exchanged water to 100 Brucine denaturedalcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylene hydrogenatedcastor oil 1 Methyl paraben 0.2 Lactic acid 0.006 Sodium lactate 0.2Photo-stabilizer (See Table 17 to 22) See Table 17 to 22 Perfume (SeeTable 17 to 22) 0.03 Total 100

Each test sample was prepared. Change of smell of sample exposed tosunlight (80 MJ) was observed (judgement by perfumier).

Table 17 shows the result of combining of natural perfume and variousphotostabilizers.

TABLE 17 Sunlight exposure Test Natural (80 MJ) exam- perfumePhotostabilizer Smell ple Name Name Amount evaluation 183 Rose oil No 0C 184 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 1852-Hydroxy-4-methoxybenzo- 0.05 B phenone 186 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 187 Octyl p-methoxycinnamate 0.05 C188 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 189 Jasmine No 0 C190 oil 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 1912-Hydroxy-4-methoxybenzo- 0.05 B phenone 192 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 193 Octyl p-methoxycinnamate 0.05 C194 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 195 Neroli oil No0 C 196 4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 1972-Hydroxy-4-methoxybenzo- 0.1 B phenone 198 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 199 Octyl p-methoxycinnamate 0.1 C 2004-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 201 Lavender No 0 C 202oil 4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2032-Hydroxy-4-methoxybenzo- 0.1 B phenone 204 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 204 Octyl p-methoxycinnamate 0.1 C 2054-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 206 Ylang No 0 C 207ylang oil 4,5-Dimorpholino-3-hydroxy- 0.2 A pyridazine 2082-Hydroxy-4-methoxybenzo- 0.2 B phenone 209 2-Hydroxy-4-methoxybenzo-0.2 B phenone-5-sodium sulfonate 210 Octyl p-methoxycinnamate 0.2 C 2114-tert-Butyl-4′-methoxy- 0.2 B di-benzoylmethane Smell evaluation  A: Nochange  B: No almost change  C: Yes change

Table 17 shows that the change of smell in a pyridazine derivative(4,5-dimorpholino-3-hydroxypyridazine) of the present invention is verysmall in comparison with other photostabilizers. Accordingly, it isunderstood that pyridazine derivative of the present invention has anexcellent photostabilization effect for natural purfume.

Table 18 shows the result of combining synthetic perfume and variousphotostabilizers.

TABLE 18 Sunlight exposure Test Synthetic (80 MJ) exam- perfumePhotostabilizer Smell ple Name Name Amount evaluation 212 Limonene No 0C 213 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 2142-Hydroxy-4-methoxybenzo- 0.05 B phenone 215 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 216 Octyl p-methoxycinnamate 0.05 C217 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 218 Linalool No 0C 219 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 2202-Hydroxy-4-methoxybenzo- 0.05 B phenone 221 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 222 Octyl p-methoxycinnamate 0.05 C223 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 224 Citral No 0 C225 4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2262-Hydroxy-4-methoxybenzo- 0.1 B phenone 227 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 228 Octyl p-methoxycinnamate 0.1 C 2294-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 230 Linalyl No 0 C 231acetate 4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2322-Hydroxy-4-methoxybenzo- 0.1 B phenone 233 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 234 Octyl p-methoxycinnamate 0.1 C 2354-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 236 Rose No 0 C 237oxide 4,5-Dimorpholino-3-hydroxy- 0.2 A pyridazine 2382-Hydroxy-4-methoxybenzo- 0.2 B phenone 239 2-Hydroxy-4-methoxybenzo-0.2 B phenone-5-sodium sulfonate 240 Octyl p-methoxycinnamate 0.2 C 2414-tert-Butyl-4′-methoxy- 0.2 B di-benzoylmethane Smell evaluation  A: Nochange  B: No almost change  C: Yes change

Table 18 shows that the change of smell in a pyridazine derivative(4,5-dimorpholino-3-hydroxypyridazine) of the present invention is verysmall in comparison with other photostabilizers. Accordingly, it isunderstood that pyridazine derivatives of the present invention have anexcellent photostabilization effect for synthetic purfume.

Table 19 shows the result of combining base perfume and variousphotostabilizers.

TABLE 19 Sunlight exposure Test Base (80 MJ) exam- perfumePhotostabilizer Smell ple Name Name Amount evaluation 242 Rose No 0 C243 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 2442-Hydroxy-4-methoxybenzo- 0.05 B phenone 245 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 246 Octyl p-methoxycinnamate 0.05 C247 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 248 Muguet No 0 C249 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 2502-Hydroxy-4-methoxybenzo- 0.05 B phenone 251 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 252 Octyl p-methoxycinnamate 0.05 C253 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 254 Woody No 0 C255 4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2562-Hydroxy-4-methoxybenzo- 0.1 B phenone 257 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 258 Octyl p-methoxycinnamate 0.1 C 2594-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 300 Fruity No 0 C 3014,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 3022-Hydroxy-4-methoxybenzo- 0.1 B phenone 303 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 304 Octyl p-methoxycinnamate 0.1 C 3054-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 306 Spicy No 0 C 3074,5-Dimorpholino-3-hydroxy- 0.2 A pyridazine 3082-Hydroxy-4-methoxybenzo- 0.2 B phenone 309 2-Hydroxy-4-methoxybenzo-0.2 B phenone-5-sodium sulfonate 310 Octyl p-methoxycinnamate 0.2 C 3114-tert-Butyl-4′-methoxy- 0.2 B di-benzoylmethane Smell evaluation  A: Nochange  B: No almost change  C: Yes change

Table 19 shows that the change of smell in a pyridazine derivative(4,5-dimorpholino-3-hydroxypyridazine) of the present invention is verysmall in comparison with other photostabilizers. Accordingly, it isunderstood that pyridazine derivatives of the present invention have anexcellent photo stabilization effect for base perfume.

Next, the inventors have studied the effective amount of photostabilizerfor perfume. Table 20 shows the result of combining a pyridazinederivative of the present invention and natural perfume.

TABLE 20 Sunlight exposure Test Natural perfume Photostabilizer (80 MJ)example Name Name Amount evaluation 312 Tuberose oil 4,5-Dimorpholino-0.03 A 313 3-hydroxypyridazine 0 C 314 Clary sage oil 0.03 A 315 0 C 316Cloves oil 0.03 A 317 0 C 318 Peppermint oil 0.03 A 319 0 C 320 Geraniumoil 0.03 A 321 0 C 322 Patchouli oil 0.01 A 323 0 C 324 Sandals wood oil0.01 A 325 0 C 326 Cinnamon oil 0.01 A 327 0 C 328 Coriander oil 0.01 A329 0 C 330 Nutmeg oil 0.01 A 331 0 C 332 Pepper oil 0.001 A 333 0 C 334Lemon oil 0.001 A 335 0 C 336 Orange oil 0.1 A 337 0 C 338 Bergamot oil0.1 A 339 0 C 340 Opopanax oil 0.1 A 341 0 C 342 Vetiver oil 0.2 A 343 0C 344 Orris oil 0.2 A 345 0 C 346 Oakmoss oil 0.2 A 347 0 C 348 Moss oil0.2 A 349 0 C 350 Civet oil 0.2 A 351 0 C 352 Castoreum oil 0.3 A 353 0C 354 Ambergris oil 0.3 A 355 0 C Smell evaluation  A: No change  B: Noalmost change  C: Yes change

Table 20 shows that approximately 0.001 wt % to approximately 0.3 wt %of a pyridazine derivative of the present invention is effective as aphotostabilizer in approximately 0.03 wt % of natural perfume.

Next, Table 21 shows the result of combining a pyridazine derivative ofthe present invention and synthetic perfume.

TABLE 21 Sunlight exposure (80 MJ) Test Synthetic perfumePhotostabilizer Smell example Name Name Amount evaluation 356β-Caryophyllene 4,5-Dimorpholi- 0.01 A 357 -no-3-hydroxy- 0 C 358cis-3-Hexenol pyridazine 0.01 A 359 0 C 360 Farnesol 0.01 A 361 0 C 362β-Phenylethyl 0.03 A 363 alcohol 0 C 364 2,6-Nonadienal 0.03 A 365 0 C366 α-Hexyl cinnamic 0.03 A 367 aldehyde 0 C 368 β-Ionone 0.05 A 369 0 C370 I-Carvone 0.05 A 371 0 C 372 Cyclopentadecanone 0.05 A 373 0 C 374Benzyl benzoate 0.1 A 375 0 C 376 γ-Undecalactone 0.1 A 377 0 C 378Eugenol 0.1 A 379 0 C 380 Indole 0.2 A 381 0 C 382 Phenylacetaldehyde0.2 A 383 dimethyl acetal 0 C 386 Lyral 0.3 A 387 0 C 388 Lilial 0.3 A389 0 C Smell evaluation  A: No change  B: No almost change  C: Yeschange

Table 21 shows that approximately 0.01 wt % to approximately 0.3 wt % ofa pyridazine derivative of the present invention is effective as aphotostabilizer for approximately 0.03 wt % of synthetic perfume.

Next, Table 22 shows the result of combining a pyridazine derivative ofthe present invention and a base perfume.

TABLE 22 Base Sunlight exposure Test perfume Photostabilizer (80 MJ)example Name Name Amount Smell evaluation 390 Jasmine 4,5-Dimorpholino-0.01 A 391 3-hydroxypyridazine 0 C 392 Chypre 0.01 A 393 0 C 394 Citrus0.03 A 395 0 C 396 Green 0.05 A 397 0 C 398 Fougere 0.1 A 399 0 C 400Oriental 0.1 A 401 0 C 402 Aldehyde 0.2 A 403 0 C 404 Animal 0.3 A 405 0C Smell evaluation  A: No change  B: No almost change  C: Yes change

Table 22 shows that approximately 0.01 wt % to approximately 0.3 wt % ofa pyridazine derivative of the present invention is effective as aphotostabilizer for approximately 0.03 wt % of base perfume.

Next, the photo stabilization effect and changes in appearance in drugcompositions were studied according to the following evaluationformulation.

Formulation For Evaluation Of Drug Stabilization Effect

Material Amount (wt %) Ion-exchanged water to 100 Brucine denaturedalcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylene hydrogenatedcastor oil 1 Methyl paraben 0.2 Lactic acid 0.006 Sodium lacate 0.2Stabilizer (See Table 23) See Table 23 Drug (see Table 23) See Table 23Total 100

Each test sample was prepared. Appearance changes of the samples exposedto sunlight (80 MJ) was observed (visual evaluation). Also, residualyield was measured by liquid chromatography.

Next, Table 23 shows the result of combining a pyridazine derivative ofthe present invention and a drug.

TABLE 23 Sunlight exposure (80 MJ) Test Drug Photostabilizer Residualyield Example Name Amount Name Amount [%] Appearance 406 Salicylic acid0.1 No 0 87.6 C 407 4,5-Dimorpholino-3-hydroxypyridazine 0.05 100.3 A408 2-Hydroxy-4-methoxybenzophenone 0.05 98.2 B 4092-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 98.0 B 410 Octylp-methoxycinnamate 0.05 92.2 C 4114-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 97.2 B 412 Dipotassiumglycyrrhizinate 0.05 No 0 85.1 C 4134,5-Dimorpholino-3-hydroxypyridazine 0.05 100.3 A 4142-Hydroxy-4-methoxybenzophenone 0.05 97.8 B 4152-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 97.5 B 416 Octylp-methoxycinnamate 0.05 90.8 C 4174-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 96.6 B 418 L-ascorbicacid 2-(dl-α- 0.01 No 0 69.0 C 419 tocopheryl hydrogen4,5-Dimorpholino-3-hydroxypyridazine 0.05 99.4 A 420 phosphate)potassium salt 2-Hydroxy-4-methoxybenzophenone 0.05 95.4 B 4212-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 95.0 B 422 Octylp-methoxycinnamate 0.05 82.1 C 4234-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 94.5 B 4242-o-α-α-glucopyranosyl- 2.0 No 0 84.7 C 425 L-ascorbic acid4,5-Dimorpholino-3-hydroxypyridazine 0.05 99.3 A 4262-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 97.8 B 4272-Hydroxy-4-methoxybenzophenone 0.05 97.3 B 428 Octyl p-methoxycinnamate0.05 92.3 C 429 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 97.0 B430 Dibutylhydroxytoluene 0.01 No 0 48.0 C 4314,5-Dimorpholino-3-hydroxypyridazine 0.05 98.8 A 4322-Hydroxy-4-methoxybenzophenone 0.05 95.2 B 4332-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 94.8 B 434 Octylp-methoxycinnamate 0.05 71.7 C 4354-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 95.2 B Appearance  A: Nochange  B: No almost change  C: Yes change

Table 23 shows that residual yield of a drug combined with a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention is very high in comparison with other photostabilizers. Also,appearance changes of the composition is small. Accordingly, it isunderstood that pyridazine derivatives of the present invention have anexcellent photostabilization effect on drugs.

The inventors have attempted to improve the photostabilzation effect bycombining the composition with sequestering agent.

First of all, the photostabilization effect and appearance changes of acomposition for each pigment were studied by the following evaluationformulation.

Formulation For Evaluation Of Pigment Stabilization Effect

(Sequestering agent combination)

Material Amount (wt %) Ion-exchanged water to 100 Brucine denaturedalcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylene hydrogenatedcastor oil 1 Methyl paraben 0.2 Lactic acid 0.006 Sodium lacate 0.2Sequestering agent (See Table 24 to 26) See Table 24 to 264,5-Dimorpholino-3-hydroxypyridazine See Table 24 to 26 Pigment (seeTable 24 to 26) See Table 24 to 26 Total 100

Each test sample was prepared. Observation of appearance changes (visualevaluation) and measurement of color difference (ΔE) were carried outfor samples exposed to sunlight (around 80 MJ).

Color difference was measured by Lab coordinate system withspectrophotometer. Color difference was calculated based on the colorbefore sunlight exposure. Namely, from the measured value (L₁,a₁,b₁)before sunlight exposure, color difference (ΔE) was calculated byfollowing formula.

ΔE={(L₂−L₁)²+(a₂−a₁)²+(b₂−b₁)² }^(½)

Table 24 and Table 25 shows the result of combining a single pigment, apyridazine derivative of the present invention and various sequesteringagents.

TABLE 24 Photo- Sunlight Test Colorant Sequestering Agent stabilizerexposure (80 MJ) Example Name Amount Name Amount Amount ΔE Appearance436 Red No. 227 0.0001 — 0 0 1.45 C 437 (D&C Red No. 33) 0.01 0.98 B 438(Trade name: Fast Acid Magenta) Trisodium ethylenediamine 0.02 0 1.40 C439 tetraacetate 0.01 0.62 A 440 Sodium metaphosphate 0.02 0 1.37 C 4410.01 0.84 B 442 Trisodium hydroxyethyl 0.02 0 14.3 C 443 ethylenediaminetriacetate 0.01 0.58 A 444 Red No. 106 0.0001 — 0 0 3.04 C 445 (Tradename: Acid Red 52) 0.02 1.23 B 446 Trisodium ethylenediamine 0.02 0 2.98C 447 tetraacetate 0.02 0.84 A 448 Sodium metaphosphate 0.02 0 2.88 C449 0.02 0.77 A 450 Sodium polyphosphate 0.02 0 2.92 C 451 0.02 0.85 A452 Yellow No. 203 0.001 — 0 0 2.77 C 453 (D&C Yellow No. 10 0.01 0.95 B454 (Trade name: Quinoline Yellow WS) Trisodium ethylenediamine 0.02 02.73 C 455 tetraacetate 0.01 0.28 A 456 Sodium metaphosphate 0.02 0 2.74C 457 0.01 0.22 A 458 Trisodium hydroxyethyl 0.02 0 2.68 C 459ethylenediamine triacetate 0.01 0.25 A 460 Yellow No. 5 0.001 — 0 0 1.83C 461 (FD&C Yellow No. 6) 0.01 0.61 B 462 (Trade name: Sunset YellowFCF) Trisodium ethylenediamine 0.02 0 1.75 C 463 tetraacetate 0.01 0.32A 464 Sodium metaphosphate 0.02 0 1.77 C 465 0.01 0.36 A 466 Sodiumpolyphosphate 0.02 0 1.75 C 467 0.01 0.33 A Smell evaluation  A: Nochange  B: No almost change  C: Yes change

TABLE 25 Photo- Sunlight Test Colorant Sequestering Agent stabilizerexposure (80 MJ) Example Name Amount Name Amount Amount ΔE Appearance468 Blue No. 1 0.0001 — 0 0 8.92 C 469 (FC&C Blue No. 1) 0.02 1.74 B 470(Trade name: Brilliant Blue FCF) Trisodium ethylenediamine 0.03 0 8.50 C471 tetraacetate 0.02 1.18 A 472 Sodium metaphosphate 0.03 0 8.02 C 4730.02 1.00 A 474 Trisodium hydroxyethyl 0.03 0 7.92 C 475 ethylenediaminetriacetate 0.02 1.08 A 476 Green No. 3 0.0001 — 0 0 2.12 C 477 (FD&CGreen No. 3) 0.02 0.75 B 478 (Trade name: Fast Green FCF) Trisodiumethylenediamine 0.03 0 2.08 C 479 tetraacetate 0.02 0.48 A 480 Sodiummetaphosphate 0.03 0 2.02 C 481 0.02 0.28 A 482 Sodium polyphosphate0.03 0 2.1 C 483 0.02 0.52 A 484 Red No. 213 0.0001 — 0 0 3.79 C 485(FD&C Red No. 19) 0.03 2.12 B 486 (Trade name: Rhodamine B) Trisodiumethylenediamine 0.05 0 3.66 C 487 tetraacetate 0.03 1.45 A 488 Sodiummetaphosphate 0.05 0 3.71 C 489 0.03 1.38 A 490 Trisodium hydroxyethyl0.05 0 3.72 C 491 ethylenediamine triacetate 0.03 1.41 A 492 Red No. 4010.001 — 0 0 7.58 C 493 (Ext. D&C Red No. 3) 0.03 0.95 A 494 (Trade name:Violamine R) Trisodium ethylenediamine 0.1 0 7.22 C 495 tetraacetate0.03 0.71 A 496 Sodium metaphosphate 0.1 0 7.07 C 497 0.02 0.66 A 498Sodium polyphosphate 0.1 0 7.14 C 499 0.02 0.78 A Smell evaluation  A:No change  B: No almost change  C: Yes change

Next, Table 26 is the results in compositions having various pigments, apyridazine derivative of the present invention and various kinds ofsequestering agents.

TABLE 26 Photo- Sunlight Test Colorant Sequestering Agent stabilizerexposure (80 MJ) Example Name Amount Name Amount Amount ΔE Appearance500 Red No. 227 0.0001 — 0 0 1.59 C 501 (Trade name: Fast Acid Magenta)0.02 1.02 B 502 Yellow No. 5 0.0001 Trisodium ethylenediamine 0.02 01.55 C 503 (Trade name: Sunset Yellow FCF) tetraacetate 0.02 0.71 A 504Red No. 227 0.0001 — 0 0 3.05 C 505 (Trade name: Fast Acid Magenta) 0.051.55 A 506 Yellow No. 203 0.0001 Sodium metaphosphate 0.02 0 3.01 C 507(Trade name: Quinoline Yellow WS) 0.05 1.01 A 508 Red No. 106 0.00001 —0 0 3.77 C 509 (Trade name: Acid Red 52) 0.02 1.10 A 510 Yellow No. 2030.0001 Trisodium hydroxyethyl 0.02 0 3.56 C 511 (Trade name: QuinolineYellow WS) ethylenediamine triacetate 0.02 0.75 A 512 Red No. 1060.00001 — 0 0 4.45 C 513 (Trade name: Acid Red 52) 0.02 1.33 B 514Yellow No. 5 0.0001 Trisodium ethylenediamine 0.02 0 4.26 C 515 (Tradename: Sunset Yellow FCF) tetraacetate 0.02 0.98 A 516 Yellow No. 2030.0001 — 0 0 1.45 C 517 (Trade name: Quinoline Yellow WS) 0.02 0.78 A518 Yellow No. 5 0.0001 Sodium metaphosphate 0.01 0 1.44 C 519 (Tradename: Sunset Yellow FCF) 0.02 0.48 A 520 Red No. 213 0.00001 — 0 0 3.89C 521 (Trade name: Rhodamine B) 0.02 1.88 B 522 Blue No. 1 0.00001Trisodium hydroxyethyl 0.03 0 3.85 C 523 (Trade name: Brilliant BlueFCF) ethylenediamine triacetate 0.02 1.22 A 524 Red No. 401 0.0001 — 0 03.04 C 525 (Trade name: Violamine R) 0.02 1.36 A 526 Blue No. 1 0.00001Trisodium ethylenediamine 0.03 0 3.02 C 527 (Trade name: Brilliant BlueFCF) tetraacetate 0.02 0.88 A 528 Red No. 401 0.0001 — 0 0 4.54 C 529(Trade name: Violamine R) 0.02 1.45 B 530 Green No. 3 0.00001 Sodiummetaphosphate 0.03 0 4.23 C 531 (Trade name: Fast Green FCF) 0.02 0.73 ASmell evaluation  A: No change  B: No almost change  C: Yes change

Tables 24 to 26 show that color difference ΔE for compositions havingpyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) of thepresent invention and a sequestering agent is very small in comparisonwith color difference ΔE for other compositions not having asequestering agent. Also, the change of appearance of the composition issmall. Accordingly, it is understood that pyridazine derivatives of thepresent invention have a better photostabilization effect for pigmentwhen combined with a sequestering agent.

Also, since a sequestering agent itself does not have aphotostabilization effect, combining a pyridazine derivative of thepresent invention and a sequestering agent has synergisticphotostabilization effect.

Next, for combinations with sequestering agent, photostabilizationeffect for each perfume was studied by the following evaluationformulation.

Formulation For Evaluation Of Perfume Stabilization Effect

(Sequestering agent combination)

Material Amount (wt %) Ion-exchanged water to 100 Brucine denaturedalcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylene hydrogenatedcastor oil 1 Methyl paraben 0.2 Lactic acid 0.006 Sodium lacate 0.2Sequestering agent (See Table 27 to 29) See Table 27 to 294,5-Dimorpholino-3-hydroxypyridazine See Table 27 to 29 Perfume (SeeTable 27 to 29) 0.03 Total 100

Each test sample was prepared. Smell change of samples exposed tosunlight (80 MJ) was observed (judgement by perfumier).

Table 27 shows the result of combining natural perfume, a pyridazinederivative of the present invention and various sequestering agents.

TABLE 27 Sunlight exposure Test Natural Photo- (80 MJ) exam- perfumeSequestering agent stabilizer Smell ple Name Name Amount Amountevaluation 532 Rose oil — 0 0 C 533 0.02 B 534 Trisodium 0.03 0 C 535ethylenediamine 0.02 A tetraacetate 536 Jasmine — 0 0 C 537 oil 0.02 B538 Sodium 0.03 0 C 539 metaphosphate 0.02 A 540 Lavender — 0 0 C 541oil 0.02 B 542 Trisodium 0.03 0 C 543 hydroxyethyl 0.02 Aethylenediamine triacetate 544 Pepper- — 0 0 C 545 mint oil 0.01 B 546Trisodium 0.03 0 C 547 ethylenediamine 0.01 A triacetate 548 Orange oil— 0 0 C 549 0.05 B 550 Sodium 0.03 0 C 551 metaphosphate 0.05 A 552Ylang — 0 0 C 553 ylang oil 0.02 B 554 Trisodium 0.03 0 C 555hydroxyethyl 0.02 A ethylenediamine triacetate 556 Bergamot — 0 0 C 557oil 0.05 B 558 Trisodium 0.03 0 C 559 ethylenediamine 0.05 Atetraacetate 560 Musk oil — 0 0 C 561 0.1 B 562 Sodium 0.03 0 C 563metaphosphate 0.1 A Smell evaluation  A: No change  B: No almost change C: Yes change

Table 27 shows that smell change of a composition including a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention and a sequestering agent is very small in comparison withsmell change of other compositions not having sequestering agent.Accordingly, it is understood that a pyridazine derivative of thepresent invention has a better photostabilization effect for naturalperfume by combining it with a sequestering agent.

Also, since the sequestering agent itself does not have aphotostabilization effect, combining a pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

Table 28 shows the result of combining a synthetic perfume, a pyridazinederivative of the present invention and various sequestering agents.

TABLE 28 Test Synthetic perfume Sequestering agent PhotostabilizerSunlight exposure (80 MJ) example Name Name Amount Amount Smellevaluation 564 Limonene — 0 0 C 565 0.02 B 566 Trisodium hydroxyethyl0.03 0 C 567 ethylenediamine triacetate 0.02 A 568 cis-3-Hexenol — 0 0 C569 0.02 B 570 Trisodium ethylenediamine 0.03 0 C 571 tetraacetate 0.02A 572 Citral — 0 0 C 573 0.01 B 574 Trisodium hydroxyethyl 0.03 0 C 575ethylenediamine triacetate 0.01 A 576 β-ionone — 0 0 C 577 0.01 B 578Trisodium ethylenediamine 0.03 0 C 579 tetraacetate 0.01 A 580 Oranthiol— 0 0 C 582 0.05 B 583 Sodium metaphosphate 0.03 0 C 584 0.05 A 585Benzyl benzoate — 0 0 C 585 0.02 B 586 Trisodium hydroxyethyl 0.03 0 C587 ethylenediamine triacetate 0.02 A 588 Rose oxide — 0 0 C 589 0.05 B590 Trisodium ethylenediamine 0.03 0 C 591 tetraacetate 0.05 A 592Lilial — 0 0 C 593 0.1 B 594 Sodium metaphosphate 0.03 0 C 595 0.1 ASmell evaluation  A: No change  B: No almost change  C: Yes change

Table 28 shows that smell change of a composition including a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention and a sequestering agent is very small in comparison withsmell change of other compositions not having a sequestering agent.Accordingly, it is understood that a pyridazine derivative of thepresent invention has a better photostabilization effect for syntheticperfume by combining it with a sequestering agent.

Also, since the sequestering agent itself does not have aphotostabilization effect, combining of a pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

Table 29 shows the result of combining a base perfume, a pyridazinederivative of the present invention and various sequestering agents.

TABLE 29 Test Synthetic perfume Sequestering agent PhotostabilizerSunlight exposure (80 MJ) example Name Name Amount Amount Smellevaluation 596 Rose — 0 0 C 597 0.02 B 598 Trisodium hydroxyethyl 0.03 0C 599 ethylenediamine triacetate 0.02 A 600 Jasmine — 0 0 C 601 0.02 B602 Trisodium ethylenediamine 0.03 0 C 603 tetraacetate 0.02 A 604Muguet — 0 0 C 605 0.02 B 606 Sodium metaphosphate 0.03 0 C 607 0.02 A608 Green — 0 0 C 609 0.01 B 610 Trisodium hydroxyethyl 0.03 0 C 611ethylenediamine triacetate 0.01 A 612 Oriental — 0 0 C 613 0.01 B 614Trisodium ethylenediamine 0.03 0 C 615 tetraacetate 0.01 A 616 Fruity —0 0 C 617 0.03 B 618 Sodium metaphosphate 0.03 0 C 619 0.03 A 620Aldehyde — 0 0 C 621 0.05 B 622 Trisodium hydroxyethyl 0.03 0 C 623ethylenediamine triacetate 0.05 A 624 Animal — 0 0 C 625 0.1 B 626Trisodium ethylenediamine 0.03 0 C 627 tetraacetate 0.1 A Smellevaluation  A: No change  B: No almost change  C: Yes change

Table 29 shows that smell change of a composition including a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention and a sequestering agent is very small in comparison withsmell change of other compositions not having a sequestering agent.Accordingly, it is understood that a pyridazine derivative of thepresent invention has a better photostabilization effect for baseperfume by combining it with a sequestering agent.

Also, since the sequestering agent itself does not have aphotostabilization effect, combining a pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

Next, when combined with a sequestering agent, the photostabilizationeffect and appearance change of a composition for each drug was studiedby the following evaluation formulation.

Formulation For Evaluation Of Drug Stabilization Effect

(Sequestering agent combination)

Material Amount (wt %) Ion-exchanged water to 100 Brucine denaturedalcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylene hydrogenatedcastor oil 1 Methyl paraben 0.2 Lactic acid 0.006 Sodium lactate 0.2Sequestering agent (See Table 30) See Table 304,5-Dimorpholino-3-hydroxypyridazine See Table 30 Drug (See Table 30)See Table 30 Total 100

Each test sample was prepared. Appearance change of the samples exposedto sunlight (around 80 MJ) was observed (visual evaluation). Also,residual yield of a drug was measured by liquid chromatography.

Next, Table 30 shows the result of combining a drug, a pyridazinederivative of the present invention and various sequestering agents.

TABLE 30 Sunlight exposure (80 MJ) Photo- Residual Test DrugSequestering Agent stabilizer yield Example Name Amount Name AmountAmount [%] Appearance 628 Salicylic acid 0.1 — 0 0 87.6 C 629 0.03 99.2B 630 Trisodium ethylenediamine 0.03 0 88.0 C 631 tetraacetate 0.03100.1 A 632 Dipotassium glycyrrhizinate 0.05 — 0 0 85.1 C 633 0.03 97.2A 634 Sodium metaphosphate 0.03 0 85.8 B 635 0.03 100.0 A 636 L-ascorbicacid 2-(dl-α-tocopheryl 0.01 — 0 0 69.0 C 637 hydrogen phosphate)potassium salt 0.03 98.5 B 638 Trisodium hydroxyethyl 0.03 0 70.1 C 639ethylenediamine triacetate 0.03 99.4 A 640 2-o-α-α-glucopyranosyl- 2.0 —0 0 84.7 B 641 L-ascorbic acid 0.03 98.3 A 642 Sodium metaphosphate 0.030 85.2 C 643 0.03 99.3 A 644 Dibutylhydroxytoluene 0.01 — 0 0 48.0 C 6450.03 95.8 B 646 Sodium metaphosphate 0.03 0 54.7 C 647 0.03 98.8 A Smellevaluation  A: No change  B: No almost change  C: Yes change

Table 30 shows that residual yield of a drug in a composition having apyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) of thepresent invention and a sequestering agent is very small in comparisonwith residual yield of a drug in other compositions not having asequestering agent. Accordingly, it is understood that pyridazinederivative of the present invention has a better photostabilizationeffect for a drug when combined with a sequestering agent.

Also, since a sequestering agent itself does not have aphotostabilization effect, combining of pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

The following are examples of external skin preparations of the presentinvention. These examples do not limit the present invention. Amountsshown are weight percent.

Example 1   Lotion (Alcohol phase) Ethanol 10.0  Oleyl alcohol 0.1Polyoxyethylene(20) sorbitan monolaurate 0.5 Polyoxyethylene(15) laurylether 0.5 4,5-Dimorpholino-3-hydroxypyridazine 5.0 Antiseptics q.s.Perfume q.s. (Water phase) 1,3-Butylene glycol 6.0 Glycerol 4.0Ion-exchanged water Balance (Manufacturing method)

Each of water phase and alcohol phase was prepared and further mixed.

Example 2  Lotion (Alcohol phase) Ethanol 10.0  Polyoxyethylene(20)oleyl ether 0.5 Antiseptics q.s. Perfume q.s. (Water phase) Dipropyleneglycol 6.0 Sorbitol 4.0 Polyethylene glycol 1500 5.04,5-Dimorpholino-3-hydroxypyridazine hydrogen chloride 20.0  Methylcellulose 0.2 Quince seed 0.1 Ion-exchanged water Balance (Manufacturingmethod)

A portion of the ion-exchanged water, methyl cellulose and quince seedwere mixed with stirring and a viscous liquid was prepared. The rest ofthe ion-exchanged water and other water phase ingredients were mixedwith dissolving. The above-mentioned viscous liquid was added to thisand a homogeneous water phase was obtained. The prepared alcohol phasewas added to the water phase and was mixed.

Example 3  Cream Stearic acid 5.0 Stearyl alcohol 4.0 Isopropylmyristate 18.0  Glyceryl monostearate 3.0 Propylene glycol 10.0 4,5-Dimorpholino-3-hydroxypyridazine 20.0  Potassium hydroxide 0.2Sodium hydrogensulfate  0.01 Antiseptics q.s. Perfume q.s. Ion-exchangedwater Balance (Manufacturing method)

Propylene glycol and potassium hydroxide were added to ion-exchangedwater and were dissolved. The mixture was heated and was kept at 70° C.(Water phase). A mixture of the other components was melted with heatingand was kept at 70° C. (Oil phase). The oil phase was gradually added tothe water phase and an emulsion was formed. After it was homogeneouslyemulsified with a homomixer, which was cooled to 30° C. with sufficientstirring.

Example 4  Cream Stearic acid 6.0 Sorbitan monostearate 2.0Polyoxyethylene(20) sorbitan monostearate 1.5 Propylene glycol 10.0 4,5-Dimorpholino-3-hydroxypyridazine 1.0 Glyceryl trioctanoate 10.0 Squalene 5.0 Sodium hydrogensulfite  0.01 Ethyl paraben 0.3 Perfume q.s.Ion-exchanged water Balance (Manufacturing method)

The propylene glycol and 4,5-dimorpholino-3-hydroxypyridazine were addedto ion-exchanged water and were dissolved. It was kept at 70° C. withheating (Water phase). A mixture of the other ingredients was meltedwith heating and was kept at 70° C. (Oil phase). The oil phase was addedgradually to the water phase and an emulsion was formed. After it wasemulsified homogeneously with a homomixer, it was cooled to 30° C. withsufficient stirring.

Example 5  Milky lotion Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum5.0 Liquid paraffin 10.0  Polyoxyethylene(10) monooleate 2.0Polyethylene glycol 1500 3.0 Triethanol amine 1.04,5-Dimorpholino-3-hydroxypyridazine hydrogen chloride 10.0  Sodiumhydrogensulfite  0.01 Ethyl paraben 0.3 Carboxyvinylpolymer  0.05Perfume q.s. Ion-exchanged water Balance (Manufacturing method)

Carboxyvinylpolymer was dissolved in a small amount of ion-exchangedwater (A phase). Polyethylene glycol 1500,4,5-dimorpholino-3-hydroxypyridazine hydrochloaide and triethanolaminewere added to the remainder of the ion-exchanged water, which wasdissolved with heating and was kept at 70° C. (Water phase). Mixture ofother ingredients was melted with heating and was kept at 70° C. (Oilphase). The oil phase was added to the water phase to form an emulsionwas formed. After A phase was added and was homogeneously emulsifiedwith a homomixer, it was cooled to 30° C. with sufficient stirring.

Example 6  Gel 95% Ethanol 10.0  Dipropylene glycol 15.0 Polyoxyethylene(50) oleyl ether 2.0 Carboxyvinylpolymer 1.0 Sodiumhydroxide  0.15 4,5-Dimorpholino-3-hydroxypyridazine 2.0 Methyl paraben0.2 Perfume q.s. Ion-exchanged water Balance (Manufacturing method)

Carboxyvinylpolymer was dissolved in ion-exchanged water homogeneously(A phase). 4,5-Dimorpholino-3-hydroxypyridazine and POE (50) oleyl etherwere dissolved in 95% ethanol, which was added to A phase. After theingredients other than sodium hydroxide were added, sodium hydroxide wasadded thereto, thereby neutralizing the composition and increasingviscosity.

Example 7  Essence (A phase) 95% Ethanol 10.0  Polyoxyethylene(20)octyldodecanol 1.0 Methyl paraben  0.15 Pantothenyl ethylether 0.1 (Bphase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropylene glycol10.0  Sodium hydrogensulfite  0.03 Carboxyvinylpolymer 0.24,5-Dimorpholino-3-hydroxypyridazine 0.1 Ion-exchanged water Balance(Manufacturing method)

Each of (A phase) and (C phase) was homogeneously dissolved. (C phase)and additive (A phase) were solubilized. Next, (B phase) was added andmixed.

Example 8  Pack (A phase) Dipropylene glycol 5.0 Polyoxyethylene(60)hydrogenated castor oil 5.0 (B phase) Olive oil 5.0 Tocopheryl acetate0.2 Ethyl paraben 0.2 Perfume 0.2 (C phase)4,5-Dimorpholino-3-hydroxypyridazine 3.0 Sodium hydrogensulfite 0.03Polyvinyl alcohol 13.0 (Saponification degree 90, Polymerization degree2000) Ethanol 7.0 Ion-exchanged water Balance (Manufacturing method)

Each of A phase, (B phase) and (C phase) was homogeneously dissolved. (Aphase) was added to (B phase) and was solubilized. Next, (C phase) wasadded and mixed.

The above-mentioned examples 1 to 7 had an excellent ultraviolet raysprevention effect. Also, in examples 1 to 8, skin trouble was notobserved at all.

Example 9   Milky lotion (Oil phase) Stearyl alcohol 1.5 Squalene 2.0Petrolatum 2.5 Hydrogenated liquid lanolin 1.5 Evening primrose oil 2.0Isopropylmyristate 5.0 Glyceryl monooleate 2.0 Polyoxyethylene(60)hydrogenated castor oil 2.0 Tocopheryl acetate 0.05 Ethyl paraben 0.2Butyl paraben 0.1 Perfume q.s. (Water phase)4,5-Dimorpholino-3-hydroxypyridazine 1.04,5-Dimorpholino-3-hydroxypyridazine hydrochloride 1.0 Sodiumhydrogensulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01Carboxyvinylpolymer 0.2 Potassium hydroxide 0.2 Ion-exchanged waterBalance (Manufacturing method)

Each of oil phase and water phase was dissolved at 70° C. Oil phase wasmixed with water phase and was emulsified with emulsifier. Next, theresult was cooled to 30° C. with a heat exchanger.

The milky lotion of example 9 had an excellent ultraviolet raysprevention effect. Also the skin trouble was not observed.

Example 10   Solid powdery foundation  (1) Talc 15.0  (2) Sericite 10.0 (3) Spherical nylon powder 10.0  (4) Porous silicic anhydride powder15.0  (5) Boron nitride 5.0  (6) Titanium dioxide 5.0  (7) Iron oxide3.0  (8) Zinc stearate 5.0  (9) 4,5-Dimorpholino-3-hydroxypyridazine 5.0(10) Liquid petrolatum Balance (11) Glyceryl triisooctanoate 15.0 (12)Sorbitan sesquioleate 1.5 (13) Antiseptics q.s. (14) Perfume q.s.(Manufacturing method)

Each of (1) to (8) was mixed with crushing. A mixture of components of(9) to (14) were added thereto and was mixed with agitation. Solidfoundation was obtained by forming to the container.

Example 11   W/O emulsion foundation  (1) Spherical nylon 10.0  (2)Porous silicic anhydride powder 8.0  (3) Titanated mica 2.0  (4)Silicone treated sericite 2.0  (5) Silicone treated mica 12.0  (6)Silicone treated titanium dioxide 5.0  (7) Silicone treated iron oxide2.0  (8) Ion-exchanged water Balance  (9)4,5-Dimorpholino-3-hydroxypyridazine 3.0 (10)Decamethylcyclopentasiloxane 18.0 (11) Dimethylpolysiloxane 5.0 (12)Squalane 1.0 (13) Polyoxyethylene denatured dimethylpolysiloxane 2.0(14) Antiseptics q.s. (15) Perfume q.s. (Manufacturing method)

Ingredients (9) to (15) were mixed and were homogeneously dissolved. Acrushed (1) to (7) were added thereto and dispersed. (8) was added tothis dispersion liquid and was emulsified. A W/O emulsion foundation wasobtained by forming to container.

Example 12   Face powder  (1) Talc Balance  (2) Sericite 10.0  (3)Spherical nylon powder 10.0  (4) Boron nitride 5.0  (5) Iron oxide 3.0 (6) Magnesium carbonate 5.0  (7) Squalane 3.0  (8) Glyceryltriisooctanoate 2.0  (9) Sorbitan sesquioleate 2.0 (10)4,5-Dimorpholino-3-hydroxypyridazine 0.1 (11) Antiseptics q.s. (12)Perfume q.s. (Manufacturing method)

Each ingredient of (1) to (6) was mixed and crushed. Mixture of eachingredient of (7) to (12) was added and mixed with agitation and a facepowder was obtained.

Example 13   Eye shadow  (1) Talc Balance  (2) Mica 15.0  (3) Sphericalnylon powder 10.0  (4) Boron nitride 5.0  (5) Iron oxide 3.0  (6)Titanium oxide coated mica 5.0  (7) Squalane 3.0  (8) Glyceryl triisooctanoate 2.0  (9) Sorbitan sesquioleate 2.0 (10)4,5-Dimorpholino-3-hydroxypyridazine 2.0 (11) Antiseptics q.s. (12)Perfume q.s. (Manufacturing method)

Components of (1) to (6) were crushed and mixed. Furthermore, a mixtureof the components of (7) to (12) was added thereto, which was mixed withagitation and an eye shadow was obtained.

Example 14   Lipstick  (1) Carnauba wax 0.5  (2) Candelilla wax 5.0  (3)Ceresin 10.0  (4) Squalane Balance  (5) Glyceryl triisostearate 10.0 (6) Glyceryl diisostearate 20.0  (7)4,5-Dimorpholino-3-hydroxypyridazine 1.0  (8) Macademia nut fatty acidcholesteryl 4.0  (9) Synthetic sodium magnesium silicate 0.5 (10)Hydrophobic silica 0.5 (11) Ion-exchanged water 2.0 (12) Colorant q.s.(13) Antiseptics q.s. (14) Perfume q.s. (Manufacturing method)

Ingredient (9) and (10) were dispersed to (8) melted at 60° C. (11) wasadded to this and was stirred sufficiently. This was added to heated anddissolved (1) to (7) and was agitated sufficiently. After (12) to (14)was added thereto which was dispersed with stirring, lipstick wasobtained by molding.

Makeup cosmetics of examples 10 to 14 have an excellent ultraviolet rayprevention effect. No skin trouble or no discoloration was observed.

Example 15  Hair form (Formulation for undiluted solution) (1) Acrylicresin/alkanolamine solution (50%) 8.0 (2) Polyoxyethylene hydrogenatedcastor oil q.s. (3) Liquid petrolatum 5.0 (4) Glycerol 3.0 (5) Perfumeq.s. (6) Antiseptics q.s. (7) Ethanol 15.0 (8)4,5-Dimorpholino-3-hydroxypyridazine 0.01 (9) Ion-exchanged waterBalance (Formulation for filling) (1) Undiluted solution 90.0 (2)Liquefied petroleum gas 10.0 (Manufacturing method)

Liquid petrolatum was added to dissolved glycerol and polyoxyethylenehydrogenated castor oil and was homogeneously emulsified with ahomomixer. This was added to solution of the other ingredients. Afterthe undiluted solution was filled a can, the valve was fixed and gas wasadded.

Example 16 Hair liquid (1) Polyoxypropylene(40) butyl ether 20.0 (2)Polyoxyethylene hydrogenated castor oil  1.0 (3) Ethanol 50.0 (4)Perfume q.s. (5) Antiseptics q.s. (6) Colorant q.s. (7)4,5-Dimorpholino-3-hydroxypyridazine  2.0 (8) Ion-exchanged waterBalance

Polyoxypropylene (40) butyl ether, polyoxyethylene hydrogenated castoroil, 4,5-dimorpholino-3-hydroxypyridadine, perfume and antiseptics weredissolved in ethanol. Colorant was dissolved in ion-exchanged water.Water phase was added to Ethanol phase and was filtered with filterpaper.

Example 17  Hair spray (Formulation of undiluted solution) (1) Acrylicresin/alkanolamine solution (50%) 7.0 (2) Cetyl alcohol 0.1 (3) Siliconeoil 0.3 (4) Ethanol Balance (5) Perfume q.s. (6)4,5-Dimorpholino-3-hydroxypyridazine 2.0 (7) Ion-exchanged water 3.0(Formulation for filling) (1) Undiluted solution 50.0 (2) Liquefiedpetroleum gas 50.0 (Manufacturing method)

Other ingredients were added to ethanol and dissolved and the result wasfiltered. After undiluted solution was added to a can and the valve wasfixed, gas was added.

Example 18  Hair tonic (1) 4,5-Dimorpholino-3-hydroxypyridazine 3.0 (2)Hydrogenated castor oil ethyleneoxide (40 mol) additives 2.0 (3) Ethanol60.0  (4) Perfume q.s. (5) Ion-exchanged water Balance (Manufacturingmethod)

The hydrogenated castor oil, ethylene oxide (40 moles) additives and4,5-dimorpholino-3-hydroxypyridazine were dissolved in ethanol. Theethanol phase and water phase were mixed and perfume was added.

The cosmetics for hair and scalp of examples 15 to 18 had an excellentultraviolet ray prevention effect. Also, scalp trouble and discolorationover of time were not observed.

Example 19  Lotion (Alcohol phase) Ethanol 10.0  Oleyl alcohol 0.1Polyoxyethylene(20) sorbitan monolaurate 0.5 Polyoxyethylene(15) laurylether 0.5 Dibutylhydroxy toluene  0.01 Antiseptics q.s. Perfume q.s.(Water phase) L-ascorbic acid 2-(dl-α-tocopheryl hydrogen phosphate) 0.02 potassium salt 4,5-Dimorpholino-3-hydroxypyridazine 1.01,3-Butylene glycol 6.0 Glycerol 4.0 Ion-exchanged water Balance(Manufacturing method)

The water phase and alcohol phase that were prepared individually weremixed.

Example 20  Cream Stearic acid 5.0 Stearyl alcohol 4.0 Isopropylmyristate 18.0  Glyceryl monostearate 3.0 Propylene glycol 10.0 4,5-Dimorpholino-3-hydroxypyridazine 0.1 L-ascorbic acid2-(dl-α-tocopheryl hydrogen phosphate)  0.01 potassium salt Potassiumhydroxide 0.2 Dibutylhydroxytoluene  0.01 Sodium hydrogensulfite  0.01Antiseptics q.s. Perfume q.s. Ion-exchanged water Balance (Manufacturingmethod)

Propylene glycol, L-ascorbic acid 2-(dl-α-tocopheryl hydrogen phosphate)potassium salt, 4,5-dimorpholino-3-hydroxypyridazine and potassiumhydroxide were added to ion-exchanged water and were dissolved. It waskept with heating at 70° C. (Water phase). Other ingredients were meltedwith heating and kept at 70° C. (Oil phase). The oil phase was addedgradually to the water phase and was emulsified preliminarily. After oilphase was added to water phase and was emulsified homogeneously with ahomomixer, it was cooled to 30° C. with sufficient stirring.

Example 21  Emulsion Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0Liquid petrolatum 10.0  Polyoxyethylene(10) monooleate 2.0 Polyethyleneglycol 1500 3.0 Triethanolamine 1.0 L-ascorbic acid 2-(dl-α-tocopherylhydrogen phosphate)  0.01 potassium salt4,5-Dimorpholino-3-hydroxypyridazine 0.1 Dibutylhydroxytoluene  0.01Ethyl paraben 0.3 Carboxyvinylpolymer  0.05 Perfume q.s. Ion-exchangedwater Balance (Manufacturing method)

Carboxyvinylpolymer was dissolved in a small amount of ion-exchangedwater (A phase). Polyethylene glycol 1500, L-ascorbic acid2-(dl-α-tocopheryl hydrogen phosphate) potassium salt,4,5-dimorpholino-3-hydroxypyridazine and triethanolamine were added tothe remainder of the ion-exchanged water. It was dissolved with heatingand was kept at 70° C. (Water phase). A mixture of other ingredients wasmelted with heating and was kept at 70° C. (Oil phase). The oil phasewas added to the water phase and was emulsified preliminarily. After Aphase was added thereto and was emulsified homogeneously with ahomomixer, which was cooled to 30° C. with sufficient stirring.

Example 22  Enamel Nitrocellulose (½ Second) 10.0 Alkyd resin 10.0Acetyltributyl citrate 5.0 4,5-Dimorpholino-3-hydroxypyridazine 0.1Ethyl acetate 20.0 Butyl acetate 20.0 Ethyl alcohol 5.0 Toluene 30.0Pigment q.s. Precipitation inhibitor q.s. (Manufacturing method)

Pigment was added to a part of acetyltributyl citrate and a part ofalkyd resin and was kneaded well (Pigment part) Other ingredients weremixed and dissolved. The pigment part was added to this, stirred well,and homogeneously dispersed.

Example 23  Transparent liquid shampoo Sodium lauryl polyoxyethylene(3)sulfate 30.0  (30% Aqueous solution) Sodium lauryl sulfate (30% Aqueoussolution) 10.0  Coconut fatty acid diethanolamide 4.0 Glycerol 1.04,5-Dimorpholino-3-hydroxypyridazine 0.1 Antiseptics q.s. colorant q.s.Perfume q.s. Sequestering agents q.s. Purified water Balance(Manufacturing method)

Each component was added to a purified water at 70° C. The mixture washomogeneously dissolved and cooled.

Example 24  Rinse Silicone oil 3.0 Liquid petrolatum 1.0 Cetyl alcohol1.5 Stearyl alcohol 1.0 Stearyltrimethyl ammonium chloride 0.74,5-Dimorpholino-3-hydroxypyridazine 0.5 Glycerol 3.0 Antiseptics q.s.Colorant q.s. Perfume q.s. Purified water Balance (Manufacturing method)

Stearyltrimethyl ammonium chloride, glycerol and pigment were added to apurified water and was kept at 70° C. (Water phase). Mixed otheringredients were dissolved with heating and was kept at 70° C. (Oilphase). The oil phase was added to the water phase. The mixture wasemulsified with a homomixer, which was cooled with stirring.

Pyridazine derivatives and salts thereof of the present invention, as anultraviolet absorbent absorbs strongly ultraviolet rays of allwavelengths with the range of 290 nm to 400 nm which reach surface ofthe earth. Accordingly, this absorbent has excellent ultraviolet rayabsorption ability. Also, thereof it has high safety and high stability.Also, pyridazine derivatives and salts of the present inventiondemonstrate an excellent effect as a photostabilizer of colorant,perfume and drug. Especially, by combining a sequestering agent, thiseffect can be synergistically enhanced. Accordingly, by combining thepyridazine derivative of the present invention, the obtained externalpreparation for the skin has high ultraviolet rays prevention effect,good stability, good safety and good photostability.

Another use other than for the external skin preparations is anultraviolet ray absorption composition which has excellent ultravioletray prevention effect.

We claim:
 1. A pyridazine derivative having a formula (1):

or its salts thereof.
 2. A method for the manufacturing pyridazinederivative or its salts according to claim 1 comprising the process ofreacting at least 10 wt % of 4,5-dichloro-3-hydroxypyridazine or4,5-dibromo-3-hydroxypyridazine or a mixture thereof, with at least 20vol % of morpholine in a reaction solution at 70° C. or higher.